Discovery of Phosphonic Acid-Containing Desaminobenzimidazoles as Fructose 1,6-Bisphosphatase Inhibitors that are Suitable for Oral Delivery via ProdrugsQun Dang1*, K. Raja Reddy2, Srinivas Rao Kasibthatla3, Tao Jiang4, Frank Taplin5, Tony Gibson5, Scott C. Potter6, Paul D. van Poelje6, M. Rami Reddy1 and Mark D. Erion1
- *Corresponding Author:
- Qun Dang
Departments of Chemistry and Biochemistry
Metabasis Therapeutics, Inc.,11119 North Torrey Pines Road
La Jolla, CA 92037, USA
E-mail: [email protected]
Received date: October 24, 2010; Accepted date: October 30, 2010; Published date: November 01, 2010
Citation: Dang Q, Reddy KR, Kasibthatla SR, Jiang T, Taplin F, et al. (2010) Discovery of Phosphonic Acid-Containing Desaminobenzimidazoles as Fructose 1,6-Bisphosphatase Inhibitors that are Suitable for Oral Delivery via Prodrugs. J Diabetes Metab 1:105. doi: 10.4172/2155-6156.1000105
Copyright: © 2010 Dang Q, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
To discover an alternative series of fructose 1,6-bisphosphatase (FBPase) inhibitors that is suitable for oral delivery via prodrugs, the 4-amino group was removed from the initial 4-aminobenzimidazole lead series, since the number of hydrogen bond donors has been suggested to affect oral bioavailability (OBAV). Several desaminobenzimidazoles were discovered as potent inhibitors of FBPase. Compound 2.8 inhibits both human and rat liver FBPase with IC 50 ’s of 0.2 and 2 μ M, respectively. Using compound 2.8 as a tool compound, various prodrugs were explored with several cyclic ester prodrugs showing >10% OBAV. The more than 5-fold improvement of OBAV indicates that removal of the 4-amino group from the 4-aminobenzimidazole scaffold renders the scaffold more suitable for oral delivery via prodrugs. Moreover, OBAV SAR suggests that both molecular weight and lipophilicity (judging by cLogP) are important factors to consider when optimizing for OBAV. ©2000 Elsevier Science Ltd. All rights reserved.